Computational investigation of circuit mechanisms underlying short-latency responses to cortical stimulation.

Transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) elicits a series of high frequency volleys termed D- and I-waves measured epidurally in the corticospinal tract of awake humans. Further, intracortical microstimulation (ICMS) in M1 of non-human primates evokes D- and I-wave responses similar to those observed in TMS. The cortical circuits and mechanisms involved in the generation of D- and I-waves by stimulation of M1 remain unclear. Here, we implemented computational models of cortical columns with laminarly-organized biophysically-based neurons, following existing models published in the literature: (1) M1 - single compartment (SC), (2) M1 - multi-compartment (MC), (3) primary auditory cortex (A1) - MC, and (4) primary somatosensory cortex (S1) - MC. The network connectivity of each model represented wiring found in the respective cortical regions. The direct effects of stimulation-induced electric fields were modeled as activation of different proportions of pyramidal neurons (PNs) across layers, and dose-response curves were constructed for layer 5 (L5) PNs. Both the M1 and A1 models reproduced D- and I-waves, with the magnitude of I-waves increasing with higher recruitment of layer 2/3 and layer 5 PNs. The S1-MC model evoked rhythmic firing activity but with timings mismatched to experimental I-waves. The models replicated the experimentally observed effects of pharmacological agents on I-waves, and virtual lesions of specific neural populations across models revealed plausible microcircuit explanations for the first and later I-waves. This comprehensive comparison of models across multiple cortical regions identified consistent mechanisms underlying the cortical response to TMS and contributes to the refinement of computational strategies for optimizing stimulation paradigms.